The Never-Ending Story on Coronary Calcium

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 13, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.02.024

EDITORIAL COMMENT

The Never-Ending Story on Coronary Calcium Is it Predictive, Punitive, or Protective?* Leslee J. Shaw, PHD,y Jagat Narula, MD, PHD,z Y. Chandrashekhar, MDx

H

igh-risk atherosclerotic plaques are patho-

increasing CAC extent represents a more advanced

logically characterized by a thin fibrous

stage of atherosclerosis and the process of calcifica-

cap and substantial plaque burden with a

tion occurs as a stabilizing force in the setting of

large necrotic core, intense macrophage infiltration,

high-risk atherosclerotic plaque characterized as

and spotty calcification (1–5). Multiple invasive imag-

echolucent or low attenuation (7). CAC may thus

ing modalities can reliably identify these markers but

have implications that are different from the prog-

their ability to predict long-term outcomes has been

nostic import of plaque volume itself.

rather modest (2,6). Noninvasive imaging modalities, such as computed tomography (CT), have been used to identify many of these high-risk plaque features (7) and reveal that coronary artery calcification (CAC) is one of the strongest predictors of future cardiac events (8). However, few studies have related CAC on CT to coronary plaque volume. Importantly, progression of CAC and overall plaque volume has potent adverse consequences (9). Furthermore, a reduction in plaque and necrotic core volume during therapy is often associated with plaque stabilization and improved outcomes, but less data are available regarding CAC in this regard. It is unknown if changes in CAC track alterations in plaque volume over time, especially following intercurrent aggressive risk factor control as a part of guideline-directed preventive therapy. It has long been speculated that although microcalcification and spotty calcification are definable components of plaque vulnerability,

CAC AND STATINS AND EVENTS Multiple observations suggest that statin therapy, which

markedly

reduces

overall

cardiovascular

events, seems to increase atherosclerotic plaque density and CAC scores on CT (1). In 1 trial substudy, CAC progression was greater in frequent versus less frequent statin users (8.2  0.5 mm 3 vs. 4.2  1.1 mm 3; p < 0.01) (2). It is, however, unclear if statins actively aid in plaque mineralization or if it is the inflammatory cell death within the lipid core that adds to the overall volume of calcified plaque and an increase in the overall CAC score (1). Beyond observations, several randomized clinical trials revealed that statin therapy did not attenuate CAC plaque progression (3). These small, intermediate outcome trials have numerous limitations but also have a consistent message. Regression or attenuation of calcified plaque has not been reported within the rigors of a clinical trial. SEE PAGE 1273

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the yDivision of Cardiology, Emory University, Atlanta, Georgia; zDivision of Cardiology, Mount Sinai Medical Center, New York,

In this issue of the Journal, Puri et al. (10) report on serial changes in coronary atheroma using intravascular ultrasound (IVUS) from 8 pooled clinical trials following high-dose, low-dose, or no-statin therapy.

New York; and the xUniversity of Minnesota/Division of Cardiology, VA

Importantly, these pooled results allow for an exam-

Medical Center Cardiology, Minneapolis, Minnesota. Dr. Narula has

ination of a decidedly larger sample of 3,495 patients,

received research grants for his institution in the form of equipment from Philips, GE Healthcare, and Panasonic Healthcare. All other authors have

including 1,545 patients receiving high-intensity

reported that they have no relationships relevant to the contents of this

statin therapy (HIST) and 1,726 patients receiving

paper to disclose.

low-intensity statin therapy (LIST), and a limited

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Shaw et al.

JACC VOL. 65, NO. 13, 2015 APRIL 7, 2015:1283–5

Never Ending Story of Coronary Calcium

sample of patients (n ¼ 224) receiving no lipid-

in predicting events is largely contained in its presence

lowering treatment. One may argue against the

and progression (12). More importantly, as a corollary,

legitimacy of combining these disparate trials with

the CAC score or its progression might not be as pre-

varying aims, statin doses, and patient populations;

dictive once plaque-altering treatment is initiated

despite the use of weighted propensity scoring tech-

(e.g., statins). In this latter setting, treatment that

niques. It is also obvious that IVUS, although used for

changes plaque volume and impacts on event occur-

this purpose in other studies, may not be the optimal

rence seems to oppose the directionality of changes in

technique for quantifying CAC. Yet, the presented

the CAC score or extent. These findings should prompt

findings are intriguing, possibly important in por-

another look into whether the strong relationship

traying CAC in a new light and certainly worthy of

between CAC progression and events stands intact

further discussion or even debate. These authors re-

during adequate statin therapy. Similarly, how much

ported that HIST elicited a marked reduction in

of the predicted risk associated with CAC scores

percent atheroma volume (p < 0.0001), as has been

(a score that is rather insensitive to modulation) is

consistently reported, whereas lesser doses of statin

contained in the risk of the extent of coronary plaque

or no-statin therapy allowed progression of atheroma

(which is a modifiable parameter) is moot. At least

volume. Interestingly, the calculation of an IVUS

among symptomatic patients in the Coronary CTA

calcium index revealed provocative findings: a sig-

Evaluation For Clinical Outcomes: An International

nificant increase in the calcium index following statin

Multicenter Registry, plaque distribution and extent

therapy (both HIST [þ0.044] and LIST [þ0.038]) far

robustly predicted all-cause mortality and myocardial

greater than that reported for the 224 patients not on

infarction, even after adjusting for CAC (13). One

statins (þ0.02). HIST had greater progression in

message from the study by Puri et al.(10) is that if CAC

calcification as compared with LIST (when both were

is reflecting the risk solely of plaque volume, the risk

compared with the small, no treatment group) that

relationship may not remain as robust once plaque is

did not reach significance between the statin groups.

modified. It is possible that once risk is detected with

There was, thus, a clear interplay between changes in

CAC, an attenuation of CAC progression may not be a

plaque volumes (and potentially events) and the

useful goal of therapy, but a reduction in events

change in CAC. CAC seemed to progress independent

should certainly be the primary focus. This explains

of change in plaque regression or progression and was

the negative clinical trials that failed to achieve their

greater with statin use. These findings partly support

primary endpoint of attenuating CAC progression

what many have posited but without definitive

following intercurrent statin use (3). A failure to

evidence.

measure coexisting noncalcified plaque burden and

These somewhat controversial findings may find

other high-risk atherosclerotic plaque features within

support from other recent work that reported disso-

prior CAC trials may have led to the fatal flaw and

ciation between the CAC score and events under

negative trial findings.

certain conditions. The Multi-Ethnic Study of Athero-

Importantly, we should only consider the current

sclerosis found that more dense plaque in the setting

results as hypothesis-generating, even though they

of more extensive CAC scores were observationally

are intriguing. They cannot infer causality and the

associated with a reduced hazard for cardiovascular

degree to which baseline clinical factors promote

events (5). It gets even more fascinating! If CAC pro-

calcification is unknown. The IVUS calcification index

gression is associated with higher event risk over time,

has multiple limitations including the fact that

its dissociation from changes in plaque volume and

severely calcified plaques were excluded. The index

events post-therapy raise important questions. CAC

is very likely a poor quantitative or comparative

may not be a monolithic unit, as is commonly

measure when compared with CT methods; it might,

conceived, and patterns of CAC (e.g., spotty calcifica-

however, have some validity in predicting directional

tion vs. more coalesced calcification) or its density

change (vs. magnitudinal alterations), because the

may have different meanings than 1 lone number (the

same index was applied serially in this pooled anal-

Agatston CAC score). It is well-substantiated that risk

ysis. Certainly, this report is worthy of additional

factors account for only a small proportion of CAC risk,

investigation.

and control of risk factors do not seem to significantly

What are possible future avenues of inquiry?

impact differences in CAC. The more recent Heinz

Further investigation is warranted as to whether

Nixdorf Recall registry suggests that CAC progression

calcification within the coronary arteries can be seen

is inevitable and predictable based on age and baseline

as protective and a sign of blocking further progres-

CAC alone and is unaffected by the burden of risk

sion of high-risk, low-density plaque. Preclinical

factors (11). It might thus appear that the merit of CAC

research is revealing complex biochemical pathways

Shaw et al.

JACC VOL. 65, NO. 13, 2015 APRIL 7, 2015:1283–5

Never Ending Story of Coronary Calcium

(e.g., those switching on osteoblast transcription

without established treatment targeted to known

factors, such as Runx2, in vascular smooth muscle

atherosclerotic disease pathways that would lead to

cells) that can be modulated to attenuate or even

effective risk reduction. We are still left with the most

promote vascular mineralization as needed (14).

important question: Although CAC predicts risk, is it

Knowing what CAC means within the context of pla-

via an intrinsic property of CAC or by being a marker

que alterations will be important. These results (4)

of high-risk plaque that coronary artery mineraliza-

would also suggest, as others have postulated, that

tion is trying to stabilize? For CAC, paraphrasing

the effectiveness of risk stratification is based on the

Hamlet’s speech, “To be or not to be” and “Whether tis

concept that CAC is a bystander of coexisting high-

nobler . to suffer CAC or to take arms against its sea of

risk atherosclerotic plaque and that variable compo-

troubles,” still remains a crucial but as yet unan-

nents (i.e., density and volume) (5) of the CAC score

swered question.

may be more or less critical components of cardiac event risk. This remains a never-ending story that is

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

incompletely defined but vital to addressing the

Jagat Narula, Division of Cardiology, Mount Sinai

detection gap for atherosclerotic disease. Identifica-

Medical Center, One Gustave L. Levy Place, Box 1030,

tion of the vulnerable patient remains elusive and

New York, New York 10029. E-mail: [email protected].

REFERENCES 1. Narula J, Nakano M, Virmani R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol 2013;61:1041–51. 2. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226–35. 3. Narula J, Strauss HW. The popcorn plaques. Nat Med 2007;13:532–4. 4. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276–82. 5. Narula J, Finn AV, Demaria AN. Picking plaques that pop. J Am Coll Cardiol 2005;45:1970–3. 6. Kaul S, Narula J. In search of the vulnerable plaque: is there any light at the end of the catheter? J Am Coll Cardiol 2014;64:2519–24.

7. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 2007;50:319–26. 8. Detrano R, Guerci AD, Carr JJ. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336–45. 9. Budoff MJ, Hokanson JE, Nasir K, et al. Progression of coronary artery calcium predicts allcause mortality. J Am Coll Cardiol Img 2010;3: 1229–36. 10. Puri R, Nicholls SJ, Shao M, et al. Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol 2015;65:1273–82.

result of the Heinz Nixdorf Recall (HNR) study. Eur Heart J 2014;20:2969–80. 12. Cassidy-Bushrow AE, Bielak LF, Sheedy PF, et al. Coronary artery calcification progression is heritable. Circulation 2007;116:25–31. 13. Al-Mallah MH, Qureshi W, Lin FY, et al. Does coronary CT angiography improve risk stratification over coronary calcium scoring in symptomatic patients with suspected coronary artery disease? Results from the prospective multicenter international CONFIRM registry. Eur Heart J Cardiovasc Imaging 2014;15:267–74. 14. Pugliese G, Iacobini C, Fantauzzi CB, Menini S. The dark and bright side of atherosclerotic calcification. Atherosclerosis 2015;238:220–30.

11. Erbel R, Lehmann N, Churzidse S, et al., on behalf of the Heinz Nixdorf Recall Study Investigators. Progression of coronary artery calcification seems to be inevitable, but predictable:

KEY WORDS atherosclerotic disease, coronary calcium, prevention, progression, statins

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